Therapeutic combinations comprising a selective estrogen receptor modulator and prostaglandin E2

ABSTRACT

This invention is directed to pharmaceutical combination compositions and methods comprising (−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt thereof and PGE2 or a pharmaceutically acceptable salt thereof, methods of using such compositions and kits containing such compositions. The compositions are useful for treating musculoskeletal frailty, including osteoporosis, osteoporotic fracture, low bone mass and frailty.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority 35 U.S.C. §119(e) ofcopending U.S. Provisional Application No. 60/089,468, filed Jun. 16,1998.

BACKGROUND OF THE INVENTION

This invention relates to a pharmaceutical combination of a selectiveestrogen receptor modulator (SERM) and PGE2 or a pharmaceuticallyacceptable salt thereof that stimulates bone formation, increases bonemass and enhances bone restoration effects of PGE2. The invention alsorelates to kits containing such combinations and the use of suchcombinations to treat musculoskeletal frailty, including osteoporosis,osteoporotic fracture, low bone mass, frailty and the like in mammals,including humans. In particular, this invention relates to a combinationof(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof and PGE2 or apharmaceutically acceptable salt thereof, kits containing such acombination and the use of such a combination to treat musculoskeletalfrailty, including osteoporosis, osteoporotic fracture, low bone mass,frailty and the like in mammals, including humans.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most serious,with 5-20% of patients dying within one year, and over 50% of survivorsbeing incapacitated.

The elderly are at greatest risk of osteoporosis, and the problem istherefore predicted to increase significantly with the aging of thepopulation. Worldwide fracture incidence is forecast to increasethree-fold over the next 60 years, and one study estimates that therewill be 4.5 million hip fractures worldwide in 2050.

Although both men and women are susceptible to musculoskeletal frailty,including osteoporosis, women are at greater risk of osteoporosis thanmen. Women experience a sharp acceleration of bone loss immediatelyfollowing menopause. Other factors that increase bone loss leading toosteoporosis include smoking, alcohol abuse, a sedentary lifestyle andlow calcium intake.

Estrogen is the agent of choice in preventing osteoporosis or postmenopausal bone loss in women. In addition, Black, et al. in EP0605193A1 report that estrogen, particularly when taken orally, lowersplasma levels of LDL and raises those of the beneficial high densitylipoproteins (HDL's). Long-term estrogen therapy, however, has beenimplicated in a variety of disorders, including an increase in the riskof uterine cancer, endometrial cancer and possibly breast cancer,causing many women to either avoid this treatment or take the medicationfor only a short period of time. Although the risk of endometrial canceris thought to be reduced by a concurrent use of a progesterone, there isstill concern about possible increased risk of breast cancer with theuse of estrogen. Recently suggested therapeutic regimens, which seek tolessen the cancer risk, such as administering combinations ofprogesterone and estrogen, cause the patient to experience unacceptablebleeding. Furthermore, combining progesterone with estrogen seems toblunt the serum cholesterol lowering effects of estrogen. Thesignificant undesirable side effects associated with estrogen therapysupport the need to develop alternative therapies for osteoporosis thathave the desirable beneficial effect on serum LDL but do not causeundesirable side effects.

Recently, a number of selective estrogen receptor modulators have beenproposed for treatment of osteoporosis. It has been reported(Osteoporosis Conference Scrip No. 1812/13 Apr. 16/20, 1993, p. 29) thatraloxifene,6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene,mimics the favorable action of estrogen on bone and lipids but, unlikeestrogen, has minimal uterine stimulatory effect. [Black, L. J. et al.,Raloxifene (LY139481 Hcl) Prevents Bone Loss and Reduces SerumCholesterol Without Causing Uterine Hypertrophy in Ovariectomized Rats,J. Clin. Invest., 1994, 93:63-69 and Delmas, P. D. et al., Effects ofRaloxifene on Bone Mineral Density, Serum Cholesterol Concentration, andUterine Endometrium in Postmenopausal Women, New England Journal ofMedicine, 1997, 337:1641-1647].

Agents such as droloxifene, U.S. Pat. No. 5,254,595, prevent bone lossand thereby reduce the risk of fracture without estrogen's side effects.However, estrogen and estrogen agonists alone are only expected toreduce the fracture risk by about 50% leaving approximately 50% ofosteopenic women still at risk for an osteoporotic fracture.

Commonly assigned U.S. Pat. No. 5,552,412, which is incorporated hereinby reference, discloses SERM compounds of the formula

wherein the variables are defined as set forth therein.(−)-Cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olis an orally active, highly potent SERM which prevents bone loss,decreases total serum cholesterol, and does not have estrogen-likeuterine stimulating effects in OVX rats.

PGE2 restores bone mass by stimulating both bone formation and boneresorption. However, in ovariectomized rat skeleton, PGE2 favors boneformation over bone resorption.

Tang et al., Restoring and Maintaining Bone in Osteogenic Female RatSkeleton: I. Changes in Bone Mass and Structure, J. Bone MineralResearch 7 (9), p1093-1104, 1992 discloses data for the lose, restoreand maintain (LRM) concept, a practical approach for reversing existingosteoporosis. The LRM concept uses anabolic agents to restore bone massand architecture (+ phase) and then switches to an agent with theestablished ability to maintain bone mass, to keep the new bone (+/−phase). The rat study utilized PGE₂ and risedronate, a bisphosphonate,to show that most of the new cancellous and cortical bone induced byPGE₂ can be maintained for at least 60 days after discontinuing PGE₂ byadministering risedronate.

Shen et al., Effects of Reciprocal Treatment with Estrogen and Estrogenplus Parathyroid Hormone on Bone Structure and Strength inOvariectomized Rats, J. Clinical Investigation, 1995, 96:2331-2338discloses data for the combination and/or sequential use ofanti-resorptive agents and anabolic agents for the treatment ofosteoporosis.

SUMMARY OF THE INVENTION

This invention is directed to a pharmaceutical composition comprising:

a. a first compound, said first compound being(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof; and

b. a second compound, said second compound being PGE2 or apharmaceutically acceptable salt thereof.

This invention is further directed to a pharmaceutical composition asrecited in the immediately preceding paragraph additionally comprising apharmaceutical carrier or diluent.

This invention is still further directed to a composition as set forthin either of the first two paragraphs of this summary wherein said firstcompound is(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olD-tartrate and said second compound is PGE2 or a pharmaceuticallyacceptable salt thereof.

This invention is still further directed to a method, designated MethodA, for treating a mammal suffering from musculoskeletal frailtycomprising administering to said mammal a pharmaceutical composition asrecited in any of the first three paragraphs of this summary.

A preferred method within Method A, designated Method B, is wherein saidmammal is suffering from osteoporosis.

Another preferred method within Method A, designated Method C, iswherein said mammal is suffering from osteotomy, childhood idiopathicbone loss or bone loss associated with periodontitis.

This invention is still further directed to a method, designated MethodA¹, for treating a mammal suffering from musculoskeletal frailtycomprising administering to said mammal

a. a first compound, said first compound being(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof; and

b. a second compound, said second compound being PGE2 or apharmaceutically acceptable salt thereof.

This invention is particularly directed to a method of Method A¹ whereinthe first compound and the second compounds are administeredsubstantially simultaneously.

This invention is also particularly directed to a method of Method A¹,hereinafter termed Method D, wherein the second compound is administeredfor a period of from about three months to about three years.

This invention is more particularly directed to a method of Method Dfollowed by administration of the first compound for a period of fromabout three months to about three years without the administration ofthe second compound during the period of from about three months toabout three years.

This invention is also more particularly directed to a method of MethodD followed by administration of the first compound for a period greaterthan about three years without the administration of the second compoundduring the greater than about three year period.

This invention is also directed to a method, hereinafter termed MethodE, for treating a mammal suffering from musculoskeletal frailtycomprising administering to said mammal a therapeutically effectiveamount of a composition as recited in any of the first three paragraphsof this summary.

A preferred method within Method E is wherein bone healing followingfacial reconstruction, maxillary reconstruction or mandibularreconstruction is enhanced, vertebral synostosis is induced, long boneextension is enhanced, the healing rate of a bone graft or a long bonefracture is enhanced or prosthetic ingrowth is enhanced.

In all of the methods of this invention, it is preferred that the mammalis a human or a companion animal. The term “companion animal” refers toa household pet or other domesticated animal such as, but not limitedto, cattle, sheep, ferrets, swine, horses, poultry, fish, rabbits,goats, dogs, cats and the like. Particularly preferred companion animalsare dogs and cats.

In all of the methods of this invention, it is particularly preferredthat the mammal is a human.

This invention is also directed to a kit comprising a treatment for amammal suffering from musculoskeletal frailty comprising:

a.(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent in a first unit dosage form;

b. PGE2 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent in a second unit dosageform; and

c. a container.

This invention is particularly directed to a kit as described in theimmediately preceding paragraph wherein said first unit dosage formcomprises (−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-ol D-tartrate andsaid second compound is PGE2.

In all of the compositions, methods and kits of this invention, it isparticularly preferred that the D-tartrate salt of(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olis used.

The phrase “condition which presents with low bone mass” refers to acondition where the level of bone mass is below the age specific normalas defined in standards by the World Health Organization “Assessment ofFracture Risk and its Application to Screening for PostmenopausalOsteoporosis (1994), Report of a World Health Organization Study Group.World Health Organization Technical Series 843”. Childhood idiopathicand primary osteoporosis are also included. Included in the treatment ofosteoporosis is the prevention or attenuation of long term complicationssuch as curvature of the spine, loss of height, prosthetic surgery, andprevention of prostate malfunctioning. Also included is increasing thebone fracture healing rate and enhancing the rate of successful bonegrafts. Also included is periodontal disease and alveolar bone loss.

The phrase “condition which presents with low bone mass” also refers toa mammal known to have a significantly higher than average chance ofdeveloping such diseases as are described above including osteoporosis(e.g., post-menopausal women, men over the age of 60, and persons beingtreated with drugs known to cause osteoporosis as a side effect (such asglucocorticoid)).

Those skilled in the art will recognize that the term bone mass actuallyrefers to bone mass per unit area which is sometimes (although notstrictly correctly) referred to as bone mineral density.

The phrase “musculoskeletal frailty” refers to a condition wherein asubject has low bone mass and/or low muscle mass, and includes suchdiseases, disorders and conditions such as, but not limited to,conditions which present with low bone mass, osteoporosis, conditionswhich present with low muscle mass, osteotomy, childhood idiopathic boneloss, bone loss associated with periodontitis, bone healing followingfacial reconstruction, maxillary reconstruction, mandibularreconstruction and bone fracture. Further, musculoskeletal frailtyencompasses such conditions as interfaces between newly attachedprostheses and bone which require bone ingrowth.

The term “treating”, “treat” or “treatment” as used herein includescurative, preventative (e.g., prophylactic) and palliative treatment.

The parenthetical negative or positive sign used herein in thenomenclature denotes the direction plane polarized light is rotated bythe particular stereoisomer.

The compositions of this invention may include hydrates of the compoundsused therein.

The expression “pharmaceutically acceptable salt” refers to nontoxiccationic salts such as (but not limited to) sodium, potassium, calcium,magnesium, ammonium or protonated benzathine(N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, meglamine (N-methyl glucamine), benethamine(N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol).

The pharmaceutical compositions and methods of this invention result inhigher magnitude bone mass gain than is achievable with the same dosesof (−)- cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol as describedabove alone or PGE2 or a pharmaceutically acceptable salt thereof asdescribed above alone. Thus, combinations of the compounds of thisinvention increase bone mass and will decrease fracture rates to agreater extent than is achievable through use of either agent alone.This invention makes a significant contribution to the art by providingcompositions and methods that increase and maintain bone mass resultingin prevention, retardation, and/or regression of osteoporosis andrelated bone disorders.

Other features and advantages will be apparent from the specificationand claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION

The first compound of this invention is(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,or a pharmaceutically acceptable salt thereof, which has the structureof Formula I:

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-oland the pharmaceutically acceptable salts thereof are prepared asdescribed in commonly assigned U.S. Pat. No. 5,552,412, which isreferenced above.

(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olD-tartrate is prepared as set forth in the immediately precedingparagraph or, alternatively, as set forth in International PatentApplication Publication Number WO97/16434, designating the United Statesand which is incorporated herein by reference.

The second compound of this invention is PGE2 (Sigma Chemical Company,3050 Spruce Street, St. Louis, Mo., 63103) or a pharmaceuticallyacceptable salt thereof.

It will be recognized that PGE2 is acidic and will form a salt with apharmaceutically acceptable cation. All such salts are within the scopeof this invention and they can be prepared by conventional methods.Typical bases used to form such cationic salts are sodium hydroxide,sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide,magnesium hydroxide, calcium hydroxide, benzathine, choline,diethanolamine, piperazine and tromethamine. For example, the cationicsalts can be prepared simply by contacting the acidic and basicentities, usually in a stoichiometric ratio, in either an aqueous,non-aqueous or partially aqueous medium, as appropriate. The salts arerecovered either by filtration, by precipitation with a non-solventfollowed by filtration, by evaporation of the solvent, or, in the caseof aqueous solutions, by lyophilization, as appropriate.

In addition, when the compounds and pharmaceutically acceptable saltsthereof used in the compositions and methods of this invention formhydrates or solvates such hydrates or solvates are also within the scopeof the invention.

The pharmaceutical compositions and methods of this invention are alladapted to therapeutic use as agents that either activate bone turnoveror prevent bone resorption or increase bone formation in mammals,particularly humans. Since these functions are closely related to thedevelopment of osteoporosis and bone related disorders, combinations ofthe compounds of this invention, by virtue of their action on bone,prevent, arrest, regress or reverse osteoporosis.

The utility of the compositions and methods of the present invention asmedical agents in the treatment of musculoskeletal frailty (e.g.,conditions which present with low bone mass or low muscle mass includingosteoporosis) in mammals (e.g. humans) is demonstrated by the activityof the compounds of this invention in conventional assays as set forthin U.S. Pat. No. 5,552,412. Further evidence of the utility of theinstant combination is set forth in Example One below. Such assays alsoprovide a means whereby the activities of the compounds of thisinvention can be compared between themselves and with the activities ofother known compounds. The results of these comparisons are useful fordetermining dosage levels in mammals, including humans, for thetreatment of such diseases.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of the combination of this inventionsystemically and/or locally. These methods include oral routes,parenteral, intraduodenal routes, etc. Generally, the compounds of thisinvention are administered orally, but parenteral administration (e.g.,intravenous, intramuscular, transcutaneous, subcutaneous orintramedullary) may be utilized, for example, where oral administrationis inappropriate for the instant target or where the patient is unableto ingest the drug. The two different compounds of this invention can beco-administered simultaneously or sequentially in any order, or a singlepharmaceutical composition comprising a first compound as describedabove and a second compound as described above in a pharmaceuticallyacceptable carrier or diluent can be administered.

In any event the amount and timing of compounds administered will, ofcourse, be dependent on the subject being treated, on the severity ofthe affliction, on the manner of administration and on the judgment ofthe prescribing physician. Thus, because of patient to patientvariability, the dosages given below are a guideline and the physicianmay titrate doses of the drug to achieve the activity (e.g., bone massaugmentation) that the physician considers appropriate for theindividual patient. In considering the degree of activity desired, thephysician must balance a variety of factors such as bone mass startinglevel, age of the patient, presence of preexisting disease, as well aspresence of other diseases (e.g., cardiovascular). For example, theadministration of(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olcan provide cardiovascular benefits, particularly for post-menopausalwomen. The following paragraphs provide preferred dosage ranges for thevarious components of this invention.

An effective dosage for(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10mg/kg/day.

An effective dosage for PGE2 is in the range of 0.0001 to 10 mg/kg/day,preferably 0.001 to 1.0 mg/kg/day.

Where the D-tartrate salt or other pharmaceutically acceptable salt ofeither of the above compounds is used in this invention, the skilledperson will be able to calculate effective dosage amounts by calculatingthe molecular weight of the salt form and performing simplestoichiometric ratios. Where a pharmaceutically acceptable salt of PGE2is used in this invention, the skilled person will be able to determineeffective dosage amounts by calculating the molecular weight of the saltform and performing simple stoichiometric ratios.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds or pharmaceutically acceptable salts thereof of this inventiontogether with a pharmaceutically acceptable carrier or diluent. Thus,the compounds and pharmaceutically acceptable salts thereof of thisinvention can be administered separately or together in any conventionaloral, parenteral or transdermal dosage form. When administeredseparately, the administration of the other compound or pharmaceuticallyacceptable salt thereof of the invention follows.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds or pharmaceutically acceptable saltsthereof of this invention can be combined with various sweeteningagents, flavoring agents, coloring agents, emulsifying agents and/orsuspending agents, as well as such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. In this connection,the sterile aqueous media employed are all readily obtainable bystandard techniques well-known to those skilled in the art.

For purposes of transdermal (e.g.,topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of each active ingredient are known, or will be apparent in lightof this disclosure, to those skilled in this art. For examples, seeRemington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 19th Edition (1990).

Pharmaceutical compositions according to the invention may contain0.1%-95% of a combination of the compounds or pharmaceuticallyacceptable salts thereof of this invention, preferably 1%-70%. In anyevent, the composition or formulation to be administered will contain aquantity of the compounds or pharmaceutically acceptable salts thereofof the invention in an amount effective to treat the disease/conditionof the subject being treated.

Since the present invention relates to treatment with a combination ofthe two active ingredients which may be administered separately, theinvention also relates to combining separate pharmaceutical compositionsin kit form. The kit includes two separate pharmaceutical compositions:(−)-cis-6phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof and PGE2 or apharmaceutically acceptable salt thereof. The kit includes a containerfor containing the separate compositions such as a divided bottle or adivided foil packet, however, the separate compositions may also becontained within a single, undivided container.

Typically the kit includes directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It is desirable to provide a memory aid on a card insert, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card e.g., as follows “First Week, Monday,Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also a daily dose of SERM can consist of onetablet or capsule while a daily dose of PGE2 or a pharmaceuticallyacceptable salt thereof can consist of several tablets or capsules. Thememory aid should reflect this.

In another specific embodiment of the invention a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

EXAMPLE ONE

S-D female rats were sham-operated (n=22) or ovariectomized (OVX, n=42)at 3 months of age. Five weeks post-surgery, OVX rats were treated witheither vehicle, prostaglandin E2 (PGE2, 1 mg/kg/d (s.c.) in 20%ethanol/water),(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-ol(0.1 mg/kg/d (p.o.)), or combined PGE2 (1 mg/kg/d (s.c.)) and(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-ol(0.1 mg/kg/d (p.o.) for 5 weeks. Trabecular bone volume (TBV), percentlabeling perimeter (L.Pm), osteoclast number per mm bone surface (Oc.N)were determined in proximal tibial metaphysis by standard static anddynamic histomorphometric techniques (Parfitt A. M. et al., Bonehistomorphometry: Standardization of nomenclature, symbols, and units. JBone Miner Res 2:595-610, 1997). Initial maximal load and stiffness ofdistal femoral metaphyseal trabecular bone were determined byindentation test for the rats sacrificed at week 10 according to theknown method. (Meng, X. W. et al., Temporal expression of the anabolicaction of PTH in cancellous bone of ovariectomized rats, J Bone MinerRes 11:421-429, 1996.)

Study Results and Discussion

OVX rats resulted in significant decrease in TBV (−33%) and significantincrease in L.Pm (+48%) and Oc.N (+39%) at 5 weeks post-surgery ascompared to sham controls. Continuous decrease in TBV was seen between 5weeks and 10 weeks post-surgery in OVX rats (−20%). PGE2 at 1 mg/kg/dsignificantly increased TBV as compared to pre-treatment OVX controls(+22%) and OVX controls (+54%). However, TBV in OVX rats treated withPGE2 were still significantly lower than that in sham controls (−22%).(−)-Cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-oltreatment significantly decreased both L.Pm and Oc.N as compared to OVXcontrols. TBV in(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-oltreated rats was significantly higher than that in OVX controls and didnot differ from the pre-treatment OVX controls, indicating that(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olprevented the further trabecular bone loss induced by OVX between 5 to10 weeks post-surgery. Combination of PGE2 and(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olincreased TBV to the level of sham controls, which was significantlyhigher than that in PGE2 or(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olalone treated groups. In the combination treated group, L.Pmsignificantly decreased by 15% and Oc. N decreased by 69% as compared tothe PGE2 alone group, indicating that(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olinhibited more bone resorption than bone formation associated with OVXand PGE2; result in further increased bone mass in the OVX rats whencompared to PGE2 alone. At week 10, initial maximal load and stiffnessof distal femur decreased significantly in OVX rats as compared to shamcontrols (−66 and −56%, respectively). PGE2 or(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olalone significantly increased bone strength compared to OVX controls butwas still significantly lower than the sham controls. However, whenusing combined treatment of PGE2 and(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-ol,bone strength was completely restored to the level of sham controls.

These data show that(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olinhibits bone resorption and bone turnover, prevents further bone lossand preserves bone strength in OVX rats. Furthermore(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olpotentiates the bone restoration effects of PGE2 in establishedosteopenic, OVX rats. Thus, combination of(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8,-tetrahydronaphthalene-2-olwith PGE2 has utility in the treatment of postmenopausal bone loss.

It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodifications may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

What is claimed is:
 1. A pharmaceutical composition comprising: insynergistic effective amounts a. a first compound, said first compoundbeing(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof; and b. a second compound,said second compound being PGE2 or a pharmaceutically acceptable saltthereof.
 2. A pharmaceutical composition of claim 1 additionallycomprising a pharmaceutical carrier or diluent.
 3. A pharmaceuticalcomposition of claim 1 wherein said first compound is(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olD-tartrate and said second compound is PGE2.
 4. A method for treating amammal suffering from musculoskeletal frailty comprising administeringto said mammal a pharmaceutical composition of claim
 1. 5. A method ofclaim 4 wherein said first compound is(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olD-tartrate and said second compound is PGE2.
 6. A method of claim 4wherein said mammal is suffering from osteoporosis.
 7. A method of claim4 wherein said mammal is suffering from osteotomy, childhood idiopathicbone or bone loss associated with periodontitis.
 8. The method of claim4 wherein bone fracture, bone healing following facial reconstruction,maxillary reconstruction or mandibular reconstruction is treated,vertebral synostosis is induced or long bone extension is enhanced, thehealing rate of a bone graft is enhanced or prosthetic ingrowth isenhanced.
 9. The method of claim 8 wherein a bone fracture is treated ina human.
 10. A method of claim 6 wherein osteoporosis is treated in ahuman.
 11. A method for treating a mammal suffering from musculoskeletalfrailty comprising administering to said mammal a. a first compound,said first compound being(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof; and b. a second compound,said second compound being PGE2 or a pharmaceutically acceptable saltthereof.
 12. A method of claim 11 wherein the first compound and thesecond compound are administered substantially simultaneously.
 13. Amethod of claim 11 wherein the second compound is administered for aperiod of from about three months to about three years.
 14. A method ofclaim 13 followed by administration of the first compound for a periodof from about three months to about three years without theadministration of the second compound during the period of from aboutthree months to about three years.
 15. A method of claim 13 followed byadministration of the first compound for a period greater than aboutthree years without the administration of the second compound during thegreater than about three year period.
 16. A method of claim 11 whereinsaid mammal is suffering from osteoporosis.
 17. A method of claim 16wherein said mammal is a human.
 18. A method of claim 11 wherein saidmammal is suffering from osteotomy, childhood idiopathic bone loss orbone loss associated with periodontitis.
 19. The method of claim 11wherein bone fracture, bone healing following facial reconstruction,maxillary reconstruction or mandibular reconstruction is treated,vertebral synostosis is induced or long bone extension is enhanced, thehealing rate of a bone graft is enhanced or prosthetic ingrowth isenhanced.
 20. The method of claim 19 wherein a bone fracture is treatedin a human.
 21. A kit comprising: a.(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent in a first unit dosage form; b. PGE2 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent in a second unit dosage form; and c. acontainer.
 22. A kit of claim 21 wherein said first unit dosage formcomprises(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-olD-tartrate and said second unit dosage form comprises PGE2.